Acta Neuropathologica

, Volume 126, Issue 6, pp 881–893

Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins

  • Kohji Mori
  • Thomas Arzberger
  • Friedrich A. Grässer
  • Ilse Gijselinck
  • Stephanie May
  • Kristin Rentzsch
  • Shih-Ming Weng
  • Martin H. Schludi
  • Julie van der Zee
  • Marc Cruts
  • Christine Van Broeckhoven
  • Elisabeth Kremmer
  • Hans A. Kretzschmar
  • Christian Haass
  • Dieter Edbauer
Original Paper

DOI: 10.1007/s00401-013-1189-3

Cite this article as:
Mori, K., Arzberger, T., Grässer, F.A. et al. Acta Neuropathol (2013) 126: 881. doi:10.1007/s00401-013-1189-3

Abstract

Massive GGGGCC repeat expansion in the first intron of the gene C9orf72 is the most common known cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Despite its intronic localization and lack of an ATG start codon, the repeat region is translated in all three reading frames into aggregating dipeptide-repeat (DPR) proteins, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg). We took an antibody-based approach to further validate the translation of DPR proteins. To test whether the antisense repeat RNA transcript is also translated, we raised antibodies against the predicted products, poly-(Ala-Pro) and poly-(Pro-Arg). Both antibodies stained p62-positive neuronal cytoplasmic inclusions throughout the cerebellum and hippocampus indicating that not only sense but also antisense strand repeats are translated into DPR proteins in the absence of ATG start codons. Protein products of both strands co-aggregate suggesting concurrent translation of both strands. Moreover, an antibody targeting the putative carboxyl terminus of DPR proteins can detect inclusion pathology in C9orf72 repeat expansion carriers suggesting that the non-ATG translation continues through the entire repeat and beyond. A highly sensitive monoclonal antibody against poly-(Gly-Arg), visualized abundant inclusion pathology in all cortical regions and some inclusions also in motoneurons. Together, our data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion. Novel monoclonal antibodies against poly-(Gly-Arg) will facilitate pathological diagnosis of C9orf72 FTLD/ALS.

Keywords

Neurodegeneration C9orf72 FTLD ALS RAN translation 

Supplementary material

401_2013_1189_MOESM1_ESM.pdf (1.4 mb)
Supplementary material 1 (PDF 1412 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kohji Mori
    • 1
  • Thomas Arzberger
    • 2
    • 3
  • Friedrich A. Grässer
    • 4
  • Ilse Gijselinck
    • 5
    • 6
  • Stephanie May
    • 2
  • Kristin Rentzsch
    • 2
  • Shih-Ming Weng
    • 2
  • Martin H. Schludi
    • 2
  • Julie van der Zee
    • 5
    • 6
  • Marc Cruts
    • 5
    • 6
  • Christine Van Broeckhoven
    • 5
    • 6
  • Elisabeth Kremmer
    • 2
    • 7
    • 8
  • Hans A. Kretzschmar
    • 3
  • Christian Haass
    • 1
    • 2
    • 8
  • Dieter Edbauer
    • 1
    • 2
    • 8
  1. 1.Adolf Butenandt Institute, BiochemistryLudwig-Maximilians University MunichMunichGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  3. 3.Center for Neuropathology and Prion ResearchLudwig-Maximilians-University MunichMunichGermany
  4. 4.Institute of VirologySaarland University Medical SchoolHomburgGermany
  5. 5.Neurodegenerative Brain Diseases Group, Department of Molecular GeneticsVIBAntwerpBelgium
  6. 6.Laboratory of Neurogenetics, Institute Born-BungeUniversity of AntwerpAntwerpBelgium
  7. 7.Institute of Molecular ImmunologyHelmholtz Zentrum München, German Research Center for Environmental Health (GmbH)MunichGermany
  8. 8.Munich Cluster of Systems Neurology (SyNergy)MunichGermany

Personalised recommendations